Cytoskeleton-Membrane Uncoupling in Duchenne Muscular Dystrophy: Implications for Newborn Screening and Early...

The cytoskeleton of striated muscle integrates force transmission, mechanotransduction, and sarcolemmal stability through coordinated networks of sarcomeres, costameres, and intermediate filaments. Together, these systems establish mechanical continuity between the contractile apparatus, the sarcolemma, and the extracellular matrix. In Duchenne muscular dystrophy (DMD), loss of dystrophin disrupts cytoskeleton-membrane coupling, resulting in early mechanical instability, abnormal calcium influx, and progressive myofiber injury. Although the genetic defect is present from birth, clinical diagnosis is typically made only after substantial tissue remodeling has already occurred, highlighting a critical gap between disease onset and clinical recognition. Newborn screening now enables detection during a pre-symptomatic phase in which muscle architecture remains relatively preserved, reframing DMD as a disorder initiated by early mechanical instability within a dynamically developing tissue environment. Current therapeutic strategies, including corticosteroids, exon-skipping approaches, gene replacement therapies, and epigenetic modulation, primarily target established pathology rather than early disease mechanisms. In contrast, earlier intervention may offer the opportunity to preserve cytoskeletal integrity and stabilize the sarcolemma, thereby limiting downstream degenerative cascades. Together, these considerations support a revised framework in which cytoskeleton-membrane uncoupling represents an early and potentially actionable event in DMD pathogenesis.